Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib

Abstract

Dietary flavonoids have many healthpromoting actions, including anticancer activity via proteasome inhibition. Bortezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. IntroductionBortezomib (Velcade) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. It is the most potent antineoplastic agent for the treatment of relapsed, refractory multiple myeloma. 1 A total of 73% of patients with myeloma responded to treatment with bortezomib combined with pegylated liposomal doxorubicin. 2 However, only 4 of 15 patients with acute leukemia showed a decrease in blast count. 3 The efficacy of bortezomib in chronic lymphocytic leukemia (CLL) appears to be related to IgV(H) and BCL-6 mutational status, 4 down-regulation of CD23, and inactivation of Notch 2. 5 However, we have previously shown that all primary CLL cells were sensitive to bortezomib in vitro. Proteasome inhibition increased Bax protein accumulation and Bax activation in CLL cells. Bortezomib also increased the sensitivity of CLL cells to TNF-related apoptosis-inducing ligand-induced apoptosis. 6 Although the effectiveness of bortezomib killing of CLL cells in vitro has also been reported by other groups, 4,5 it did not display substantial antitumor activity in patients with CLL. 7,8 The basis of this differential activity of bortezomib on CLL cells in vivo and in vitro is unknown. Autologous plasma is capable of maintaining survival of CLL cells in vitro and conferring resistance to chemo-radiotherapy, 9 and albumin in plasma plays an important role in this survival mechanism. 10 We sought to identify factors in the blood, which could prevent bortezomib-mediated killing of leukemic cells in the circulation.Quercetin is one of the most abundant flavonoids in the human diet and is a potent antioxidant. 11 Quercetin, abundant in human plasma, noncovalently binds to serum albumin. 12,13 It contributes to the prevention of human diseases by promoting relaxation of cardiovascular smooth muscle and protects low-density lipoprotein from oxidation. 14 Recent studies found that quercetin can induce apoptosis by inhibiting proteasome activation, 15 causing G 2 /M-phase arrest 16 and increasing p21 expression. 17 Other dietary flavonoids, such as myricetin, kaempferol, and apigenin, also have similar functions to quercetin with respect to proteasome inhibition and apoptosis induction. 15 In this study, we demonstrate that human plasma affects killing by bortezomib and that the dietary flavonoids, especially quercetin, inhibit bortezomib-induced apoptosis in malignant B-cell lines and primary CLL cells. This inhibitory activity of quercetin was associated with complex formation with bortezomib. However, in myeloma cell lines, quercetin al...

Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma

“…For example, the flavonoid quercetin inhibits bortezomib-induced apoptosis. 40 In contrast to quercetin, we have observed that chemopreventive ITC potentiate the anti-MM effects of bortezomib, and other conventional and novel anti-MM agents. These data provide the framework for future studies of ITC in combination with currently available anti-MM agents: the observed synergy may allow for ITC to be combined with lower doses of other anti-MM agents, thus decreasing the rates and severity of side effects while maintaining potent anti-MM activity.…”

The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cellsin vitro, as a single agent and in combination with other drugs

“…This was speculated to be a result of the single agent use of bortezomib in a heavily pretreated patient population (median lines of prior therapy = four, range 2-11) (Faderl et al, 2006). Moreover, the presence of flavonoids, such as quercetin and myricetin, in the plasma have been attributed to the prevention of CLL cell death and are linked to the chemical reaction between quercetin and the boronic acid group in bortezomib (Liu et al, 2008;Wickremasinghe, 2008). Thus, PIs that do not contain a boron moiety and the partnership of these compounds with additional drugs whose activity complements theirs may be necessary to achieve clinical remission in heavily pretreated CLL patients.…”

Differential Interactions of Falcarinol Combined with Anti-Tumour Agents on Cellular Proliferation and Apoptosis in Human Lymphoid Leukaemia Cell Lines

“…Combination of histone deacetylase inhibitors (HDACis) with Bortezomib within Leukaemia cell lines has demonstrated potential to overcome resistance [41,42]. However, certain natural agents have also been shown to inhibit the actions of Bortezomib, of particular note were the inhibitory actions of the dietary Flavonoid: Quercetin, in B cell lines and primary CLL cells [43]. These potential inhibitory actions highlight the importance of identifying whether natural agents act synergistically with therapeutic agents but also to ensure that they do not inhibit their actions.…”